This study is designed to follow through on unique observations made during our last period of funding which established the importance of p16 in treatment response to photodynamic therapy (PDT). We demonstrated that ablative therapy with PDT was able to eliminate most biomarkers of neoplasia after therapy. In addition, we found that PDT is comparable to surgery in its ability to prevent esophageal adenocarcinoma related mortality. In this proposal, we will be investigating alternative forms of therapy for patients Barrett's esophagus and high-grade dysplasia that have p16 abnormalities. In order to investigate this hypothesis, we have established two specific aims. The first is to assess the effect of radiofrequency (RFA) and sodium porfimer based PDT in patients with HGD that have p16 intact in a randomized study with 20 patients per arm. The second aim will be to assess the effect of RFA and ALA based PDT in patients with Barrett's esophagus and HGD that have abnormal p16 with 30 patients per arm. RF ablation produces injury through different mechanisms and may not be influenced by p16 loss. ALA PDT relies on a pro-drug that is converted to active form within the mucosa and also is known to initiate a different mechanism of cell death compared with sodium porfimer based PDT. In this revised application, we propose to enroll 100 out of the 110 we initially proposed within a two year time frame by decreasing the period of follow-up and increasing staffing to increase patient recruitment. In the patients who receive either for of PDT, we will be assessing tissue dosimetry using a novel reflectance probe that can assess tissue scattering and absorption coefficients as well as oximetry information. We will also be assessing the quality of life after therapy using general and disease specific measures. Novel elements of this proposal include the assessment of the extent of dysplasia using an imaging technique combining high-resolution narrow band imaging and autofluorescence imaging. We will continue to assess the response to ablation therapy in these patients with our biomarkers to increase our understanding of their value in predicting the course of the disease. These studies will provide an improved understanding regarding the response of Barrett's esophagus to ablation therapy.